JP7602333B2 - Calcium phosphate composition - Google Patents

Description

The present invention relates to a calcium phosphate composition that can form a high-strength hardened body and is used for biobone reinforcement treatment in the medical field, including oral surgery.

As a bone filler for bio-bone reinforcement treatment used in the medical field including oral surgery, there is a self-setting calcium phosphate hardening composition obtained by kneading a calcium phosphate compound powder with a hardening liquid that reacts with the powder (see Patent Documents 1 to 3). This calcium phosphate hardening composition is a fluid paste or clay-like material, and has the advantage of being able to flexibly adapt to affected areas such as complex-shaped bone defects and fractures.

The calcium phosphate hardening composition is prepared, for example, by mixing and kneading a calcium phosphate compound powder with a hardening liquid in a specified ratio at the operating site, and then filling the affected area with the mixture before it hardens by injecting it with a syringe or kneading it by hand.

The powders of calcium phosphate compounds described in Patent Documents 1 to 3 contain α-type tricalcium phosphate as the main material, and the resulting hardenable calcium phosphate compositions have a short hardening time and exhibit sufficient strength for practical use as bone fillers (hardened products). For this reason, hardenable calcium phosphate compositions containing α-type tricalcium phosphate are widely used in clinical settings.

However, the bone filler (hardened material) obtained from the calcium phosphate hardening composition containing α-type tricalcium phosphate is absorbed into the bone slowly, and is not replaced by bone.

β-type tricalcium phosphate is known as a calcium phosphate that is rapidly absorbed into bone. Patent Document 4 discloses a calcium phosphate hardening composition obtained by kneading a powder containing β-type tricalcium phosphate, dicalcium phosphate, and tetracalcium phosphate with a hardening liquid, and describes that this calcium phosphate hardening composition has a short hardening time and that the resulting hardened calcium phosphate has excellent absorbability into bone.

However, calcium phosphate hardening compositions that are prepared by mixing a powder containing such a calcium phosphate compound with a hardening liquid have problems such as the powder easily flying around when the powder is filled into a special tool, and are complicated because a special hardening liquid must be prepared in addition to the powder. Therefore, there is a need to develop a calcium phosphate hardening composition with improved handling properties.

Patent No. 4111418 Patent No. 4111419 Patent No. 4134299 JP 2015-53981 A

Therefore, the object of the present invention is to provide a calcium phosphate hardening composition that has excellent handling properties and is suitable for use in biomedical bone reinforcement treatment.

As a result of intensive research in view of the above object, the present inventors have found that by mixing a first paste containing dicalcium phosphate with a second paste containing tetracalcium phosphate, and by further containing β-tricalcium phosphate only in the first paste , a calcium phosphate hardening composition having a short hardening time and excellent absorbability into bone can be obtained, and have arrived at the present invention. Note that in this application, the "calcium phosphate hardening composition" is also referred to as a "hardenable paste-like composition".

That is, the calcium phosphate composition according to the first aspect of the present invention is
A first paste and a second paste that can be hardened by mixing with the first paste,
the first paste containing dicalcium phosphate and the second paste containing tetracalcium phosphate;
The first paste is characterized in that it further contains β-type tricalcium phosphate.

In the calcium phosphate composition according to the first aspect,
The average particle size of the dicalcium phosphate in the first paste is preferably 1 to 50 μm.

In the calcium phosphate composition according to the first aspect,
The first paste preferably contains 100 parts by mass of β-type tricalcium phosphate, 4 to 10 parts by mass of dicalcium phosphate, and 25 to 45 parts by mass of water.

In the calcium phosphate composition according to the first aspect,
The second paste preferably contains 20 to 40 parts by mass of water per 100 parts by mass of tetracalcium phosphate.

In the calcium phosphate composition according to the first aspect,
The contents of β-type tricalcium phosphate, dicalcium phosphate and tetracalcium phosphate in the mixture of the first paste and the second paste are preferably 50 to 90 mass%, 2 to 10 mass% and 5 to 30 mass%, respectively, relative to 100 mass% in total of β-type tricalcium phosphate, dicalcium phosphate and tetracalcium phosphate.

In the calcium phosphate composition according to the first aspect,
It is preferable that the amount of α-type tricalcium phosphate contained in the mixture of the first paste and the second paste is 5% by mass or less of the amount of β-type tricalcium phosphate.

The calcium phosphate composition according to the second aspect of the present invention comprises:
A first paste, a second paste that is hardenable by mixing with the first paste , and a third paste;
The first paste contains dicalcium phosphate, the second paste contains tetracalcium phosphate, and the third paste contains β-tricalcium phosphate.

In the calcium phosphate composition according to the second aspect,
The average particle size of the dicalcium phosphate in the first paste is preferably 1 to 50 μm.

In the calcium phosphate composition according to the second aspect,
The contents of β-type tricalcium phosphate, dicalcium phosphate and tetracalcium phosphate in the mixture of the first paste, the second paste and the third paste are preferably 50 to 90 mass%, 2 to 10 mass% and 5 to 30 mass%, respectively, relative to 100 mass% in total of β-type tricalcium phosphate, dicalcium phosphate and tetracalcium phosphate.

In the calcium phosphate composition according to the second aspect,
It is preferable that the amount of α-type tricalcium phosphate contained in the mixture of the first paste, the second paste, and the third paste is 5% by mass or less of the amount of β-type tricalcium phosphate.

The paste material according to the first aspect of the present invention comprises:
A paste material used as a first paste of the calcium phosphate composition according to the first aspect of the present invention, comprising:
It is characterized by containing 100 parts by mass of β-type tricalcium phosphate, 4 to 10 parts by mass of dicalcium phosphate, and 25 to 45 parts by mass of water.

The paste material according to the second aspect of the present invention comprises:
A paste material used as a second paste of the calcium phosphate composition according to the first aspect of the present invention, comprising:
It is characterized by containing 100 parts by mass of tetracalcium phosphate and 20 to 40 parts by mass of water.

The cured product of the present invention is
A hardened body obtained by hardening the calcium phosphate composition according to the first and second aspects of the present invention.

The calcium phosphate composition of the present invention can produce a paste-like composition (calcium phosphate hardening composition) that can harden in a short time by mixing and kneading two or three types of paste just before use, and is therefore easy to handle. In addition, the hardened calcium phosphate material is highly absorbable into bone after hardening, making it suitable for use as a material for biomedical bone reinforcement treatment.

[1] Calcium phosphate composition
(1) First Aspect A calcium phosphate composition according to a first aspect of the present invention comprises a first paste and a second paste that can be hardened by mixing with the first paste, the first paste containing dicalcium phosphate, and the second paste containing tetracalcium phosphate.

The hardenable paste-like composition (hereinafter also referred to as the "calcium phosphate hardening composition") obtained by mixing the first and second pastes constituting the calcium phosphate composition of the present invention contains dibasic calcium phosphate and tetrabasic calcium phosphate, and therefore can easily form a calcium phosphate hardened material (bone filler). Furthermore, since the first paste and/or the second paste further contains β-type tribasic calcium phosphate, which is rapidly absorbed into bone, the formed calcium phosphate hardened material (bone filler) has excellent absorbability in bone and the hardening time of the calcium phosphate hardening composition can be shortened.

The first paste is a paste-like composition containing dicalcium phosphate, and the second paste is a paste-like composition containing tetracalcium phosphate. The first paste and the second paste are mixed to produce a calcium phosphate hardening composition. It is preferable that the first paste and/or the second paste further contain β-type tricalcium phosphate. The β-type tricalcium phosphate may be contained in the first paste, the second paste, or both the first paste and the second paste, but it is preferable that it is contained only in the first paste.

The calcium phosphate hardening composition obtained by mixing the first paste and the second paste preferably contains dibasic calcium phosphate, tetrabasic calcium phosphate, and water, and more preferably contains β-type tribasic calcium phosphate. By containing β-type tribasic calcium phosphate, the hardening time of the calcium phosphate hardening composition can be shortened, and the obtained hardened calcium phosphate (bone filler) has excellent absorbability in bone.

The content of β-type tricalcium phosphate in the calcium phosphate hardening composition is preferably 50-90% by mass, more preferably 60-80% by mass, relative to 100% by mass of the total of β-type tricalcium phosphate, dicalcium phosphate, and tetracalcium phosphate. By setting the content of β-type tricalcium phosphate within the range of 50-90% by mass, the hardened calcium phosphate formed can be made more highly resorbable in bone. In addition, the hardened calcium phosphate can be made to exhibit excellent strength.

The content of dicalcium phosphate in the calcium phosphate hardening composition is preferably 2 to 10 mass% and more preferably 4 to 7 mass% relative to 100 mass% of the total of β-type tricalcium phosphate, dicalcium phosphate, and tetracalcium phosphate. By setting the content of dicalcium phosphate within the range of 2 to 10 mass%, the hardening time of the calcium phosphate hardening composition can be reliably shortened.

The content of tetracalcium phosphate in the calcium phosphate hardening composition is preferably 5 to 30 mass% and more preferably 15 to 20 mass% relative to 100 mass% of the total of β-type tricalcium phosphate, dicalcium phosphate and tetracalcium phosphate. By setting the content of tetracalcium phosphate within the range of 5 to 30 mass%, the pH of the calcium phosphate hardening composition can be maintained in the neutral range and the hardening time can be reliably shortened.

It is preferable to adjust the content of β-type tricalcium phosphate and dicalcium phosphate in the first paste, and the content of β-type tricalcium phosphate and tetracalcium phosphate in the second paste so that the calcium phosphate hardening composition obtained when the first paste and the second paste are mixed in a predetermined ratio contains β-type tricalcium phosphate, dicalcium phosphate, and tetracalcium phosphate in the amounts described above. As described above, β-type tricalcium phosphate may be contained in either the first paste or the second paste, or in both.

The first paste preferably contains 4 to 10 parts by mass of dicalcium phosphate and 25 to 45 parts by mass of water per 100 parts by mass of β-type tricalcium phosphate, and the second paste preferably contains 20 to 40 parts by mass of water per 100 parts by mass of tetracalcium phosphate.

By setting the water content in the first paste and the second paste within the above range, the hardening reaction of the calcium phosphate hardening composition (see formula (I) described below) can be more reliably promoted. In addition, the viscosity of the first paste and the second paste can be set within an appropriate range. Furthermore, the consistency of the prepared calcium phosphate hardening composition can be more reliably set within the range described below.

The mixing ratio of the first paste to the second paste depends on the amount of each calcium phosphate contained in the first paste and the second paste, and is determined so that the amount of each calcium phosphate in the calcium phosphate hardening composition after mixing is the above-mentioned content. From the viewpoint of handling in the operating field, the mixing ratio of the first paste to the second paste is preferably in the range of 1:9 to 9:1, more preferably in the range of 2:8 to 8:2, and most preferably in the range of 3:7 to 7:3.

(2) Second Aspect A calcium phosphate composition according to a second aspect of the present invention comprises a first paste, a second paste which can be hardened by mixing with the first paste, and a third paste which promotes a hardening reaction by mixing with the first paste and the second paste, wherein the first paste contains dicalcium phosphate, the second paste contains tetracalcium phosphate, and the third paste contains β-tricalcium phosphate.

The calcium phosphate composition according to the second embodiment of the present invention is a three-paste composition obtained by dividing the calcium phosphate composition according to the first embodiment, which is a two-paste composition, and is provided with β-type tricalcium phosphate contained in the first paste and/or the second paste in the calcium phosphate composition according to the first embodiment as a third paste separate from the first and second pastes. In this way, by making the β-type tricalcium phosphate a paste separate from the dicalcium phosphate (first paste) and the tetracalcium phosphate (second paste), the storage stability of the first to third pastes before mixing can be further improved.

In the calcium phosphate composition according to the second embodiment, the hardenable paste-like composition (calcium phosphate hardening composition) obtained by mixing the first to third pastes is the same as the calcium phosphate composition according to the first embodiment except that it essentially contains β-type tricalcium phosphate, and the hardened calcium phosphate (bone filler) formed is also the same as the calcium phosphate composition according to the first embodiment. Therefore, the contents of β-type tricalcium phosphate, dicalcium phosphate and tetracalcium phosphate in the calcium phosphate hardening composition are the same as those in the calcium phosphate composition according to the first embodiment.

In the calcium phosphate composition according to the second embodiment, the first paste preferably contains 20 to 40 parts by mass of water per 100 parts by mass of dicalcium phosphate, the second paste preferably contains 20 to 40 parts by mass of water per 100 parts by mass of tetracalcium phosphate, and the third paste preferably contains 20 to 40 parts by mass of water per 100 parts by mass of β-type tricalcium phosphate.

The mixing ratio of the first paste, the second paste, and the third paste is determined so that the calcium phosphate content in the calcium phosphate hardening composition after mixing is as described above. For ease of handling in the operating field, it is preferable to set each paste to be in the range of 10 to 80 mass%, more preferably in the range of 15 to 70 mass%, and most preferably in the range of 20 to 60 mass%, when the total of the first to third pastes is 100 mass%.

(3) Calcium phosphate compounds
(a) β-Calcium Triphosphate β-Calcium Triphosphate (β- _Ca3 ( _PO4 ) ₂ ; sometimes abbreviated as β-TCP) is a calcium phosphate that is rapidly absorbed into bone. In the present invention, the calcium phosphate hardening composition is configured to contain this β-calcium triphosphate instead of α-calcium triphosphate, thereby making the resulting calcium phosphate hardened material highly absorbable in bone.

The average particle size of the β-type tricalcium phosphate powder in the first paste is preferably 1 to 100 μm. By setting the average particle size of the β-type tricalcium phosphate powder within this range, the hardening time of the calcium phosphate hardening composition can be reliably shortened. The average particle size of the β-type tricalcium phosphate powder is more preferably 2 to 30 μm. The average particle size of the β-type tricalcium phosphate powder referred to here is the average particle size in the suspension obtained by suspending the β-type tricalcium phosphate powder in water, dispersing the resulting suspension with ultrasonic waves, and then measuring the powder present in the suspension.

There is no particular limitation on the method for producing β-type tricalcium phosphate, but examples include a method in which tricalcium phosphate is produced using any of the known wet synthesis methods, dry synthesis methods, hydrothermal synthesis methods, etc., and then calcined at 750 to 1150°C to obtain β-type tricalcium phosphate.

When β-type tricalcium phosphate is produced, a small amount of α-type tricalcium phosphate may be contained as an impurity in β-type tricalcium phosphate. For example, the firing temperature is adjusted as described below, or the α-type tricalcium phosphate contained as an impurity is removed, so the content of α-type tricalcium phosphate is preferably kept below a predetermined value. The content of α-type tricalcium phosphate relative to β-type tricalcium phosphate is preferably 5% by mass or less, and more preferably 3% by mass or less. Therefore, the amount of α-type tricalcium phosphate contained in the calcium phosphate hardening composition is preferably 5% by mass or less, and more preferably 3% by mass or less, of the amount of β-type tricalcium phosphate.

The method for producing β-type tricalcium phosphate is not particularly limited, but for example, a method can be used in which β-type tricalcium phosphate is produced using any of the known wet synthesis methods, dry synthesis methods, hydrothermal synthesis methods, etc., and then fired at 750 to 1200°C. For a method for producing β-type tricalcium phosphate, see JP 2015-53981 A.

The firing temperature of the above-mentioned β-type tricalcium phosphate is preferably 940 to 1150°C, more preferably 970 to 1125°C, even more preferably 1000 to 1100°C, and even more preferably 1025 to 1075°C. By setting the temperature within such a range, production efficiency can be further improved and the amount of α-type tricalcium phosphate contained as an impurity in β-type tricalcium phosphate can be further reduced.

In the firing of the β-type tricalcium phosphate, the time from the start of heating until the firing temperature is reached (heating time) may be, for example, 2 to 12 hours. The heating time is preferably 5 to 11 hours, more preferably 6 to 10 hours, and most preferably 7 to 9 hours. By setting the heating time to such a preferred range, the amount of α-type tricalcium phosphate contained as an impurity in the β-type tricalcium phosphate can be further reduced.

In the firing of the β-type tricalcium phosphate, the time from the start of temperature reduction from the firing temperature to room temperature (temperature reduction time) may be, for example, 2 to 12 hours. The temperature reduction time is preferably 5 to 11 hours, more preferably 6 to 10 hours, and most preferably 7 to 9 hours. By setting the temperature reduction time to such a preferred range, the amount of α-type tricalcium phosphate contained as an impurity in the β-type tricalcium phosphate can be further reduced.

(b) Dicalcium phosphate Dicalcium phosphate is a calcium phosphate that reacts with tetracalcium phosphate contained in the second paste to generate amorphous hydroxyapatite and contributes to the hardening of the calcium phosphate hardening composition. The hardening mechanism of the calcium phosphate hardening composition will be described in detail later.

The average particle diameter of the dicalcium phosphate powder is preferably 1 to 50 μm. By setting the average particle diameter of the dicalcium phosphate powder within this range, the hardening time of the calcium phosphate hardening composition can be reliably shortened. The average particle diameter of the dicalcium phosphate powder is more preferably 2 to 40 μm, and even more preferably 15 to 30 μm. The average particle diameter is the average particle diameter in the suspension obtained by suspending the dicalcium phosphate powder in water, dispersing the resulting suspension with ultrasonic waves, and then measuring the powder present in the suspension.

The dicalcium phosphate may be any of dicalcium phosphate dihydrate ( _CaHPO4.2H2O ; sometimes abbreviated as DCPD) and anhydrous dicalcium phosphate (CaHPO4; sometimes abbreviated as DCPA). Commercially available products may be used as the dicalcium phosphate dihydrate and _anhydrous dicalcium phosphate.

In order to obtain the powder of dicalcium phosphate preferably used in one embodiment of the present invention, commercially available dicalcium phosphate may be pulverized using an automatic mortar or other such tool. For example, when the first paste contains dicalcium phosphate and β-type tricalcium phosphate, the mixture may be pulverized, or dicalcium phosphate alone may be pulverized before mixing dicalcium phosphate and β-type tricalcium phosphate. When it is desired to shorten the hardening time of the calcium phosphate composition obtained by mixing the pastes, it is preferable to pulverize only dicalcium phosphate first.

(c) Tetrabasic calcium phosphate Tetrabasic calcium phosphate ( _Ca4 ( _PO4 ) _2O ; sometimes abbreviated as TeCP) is a calcium phosphate that reacts with dibasic calcium phosphate to produce amorphous hydroxyapatite and contributes to the hardening of the calcium phosphate hardening composition. The hardening mechanism of the calcium phosphate hardening composition will be described in detail later.

The average particle diameter of the quaternary calcium phosphate powder is preferably 1 to 100 μm. By setting the average particle diameter of the quaternary calcium phosphate powder within this range, the hardening time of the calcium phosphate hardening composition can be reliably shortened. The average particle diameter of the quaternary calcium phosphate powder is more preferably 5 to 90 μm, more preferably 10 to 80 μm, even more preferably 30 to 70 μm, and most preferably 40 to 60 μm. The average particle diameter is the average particle diameter in the suspension obtained by suspending the quaternary calcium phosphate powder in water, dispersing the resulting suspension with ultrasonic waves, and then measuring the powder present in the suspension.

The method for producing quaternary calcium phosphate is not particularly limited, but for example, the methods described in JP-A-6-329405 and JP-A-7-315814 can be applied.

(4) Reaction of calcium phosphate hardening composition In the calcium phosphate hardening composition obtained by mixing the first paste and the second paste of the calcium phosphate composition according to the first embodiment, or in the calcium phosphate hardening composition obtained by mixing the first paste, the second paste, and the third paste of the calcium phosphate composition according to the second embodiment, the reaction of dicalcium phosphate (the following formula (I) shows the case where DCPD is used) and tetracalcium phosphate is represented by the following formula (I):
2Ca ₄ (PO ₄ ) ₂ O＋2CaHPO ₄・2H ₂ O → Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ +4H ₂ O ・・・(I)
The reaction (hydration hardening reaction) shown in FIG. 1 progresses, and amorphous hydroxyapatite is produced (precipitated).

When the calcium phosphate hardening composition contains β-type tricalcium phosphate, the amorphous hydroxyapatite powder that is generated is interposed between the particles of the β-type tricalcium phosphate powder. In this way, by being interposed between the particles of the β-type tricalcium phosphate powder, in other words being dispersed on the surfaces of adjacent powder particles, the amorphous hydroxyapatite exerts its function as a binder that connects the particles of the β-type tricalcium phosphate powder, and as a result, the calcium phosphate hardening composition hardens in a short period of time.

In other words, β-type tricalcium phosphate powder alone does not harden due to the extremely long hardening time of β-type tricalcium phosphate, but by interposing amorphous hydroxyapatite between the particles of β-type tricalcium phosphate powder, the calcium phosphate hardening composition hardens in a short period of time.

Amorphous hydroxyapatite is a calcium phosphate compound that is absorbed into bone, similar to β-type tricalcium phosphate. Therefore, the hardened calcium phosphate hardening composition containing this amorphous hydroxyapatite and β-type tricalcium phosphate (hardened calcium phosphate material) does not contain calcium phosphate compounds that are absorbed slowly into bone, such as α-type tricalcium phosphate, and has excellent absorbability in bone. Therefore, bone is regenerated as the hardened calcium phosphate material is absorbed, and the implantation site where the hardened calcium phosphate material is implanted can be replaced with regenerated bone.

Furthermore, since dibasic calcium phosphate is acidic in an aqueous dispersion and tetrabasic calcium phosphate is alkaline in an aqueous dispersion, the reaction shown in formula (I) above is a neutralization reaction. In this way, by forming a reaction system in which amorphous hydroxyapatite is obtained by a neutralization reaction, it is possible to adequately suppress or prevent the acid or alkali from remaining in the formed hardened calcium phosphate. Therefore, it is possible to adequately suppress or prevent the destruction of cells such as blood cell components caused by the leakage of acid or alkali from the hardened calcium phosphate implanted at the implantation site of the bone. Therefore, the hardening calcium phosphate composition is more excellent in safety.

As described above, the calcium phosphate composition of the present invention hardens by the reaction between the dicalcium phosphate contained in the first paste and the quaternary calcium phosphate contained in the second paste. Therefore, in order to prevent unintentional hardening before mixing, it is preferable that the first paste is substantially free of quaternary calcium phosphate. For the same reason, it is preferable that the second paste is substantially free of dicalcium phosphate.

Here, the above "substantially free" means that the amount of tetracalcium phosphate contained in the first paste is 1% by mass or less, when the total mass of the first paste is 100% by mass. More preferably, it is 0.5% by mass or less, and even more preferably, it is 0.1% by mass or less. The same applies to the amount of dicalcium phosphate contained in the second paste.

(5) Other calcium phosphate compounds The calcium phosphate composition according to the first embodiment (first paste and second paste) and the calcium phosphate composition according to the second embodiment (first paste, second paste and third paste) may contain calcium phosphate compounds such as monocalcium phosphate, amorphous hydroxyapatite, octacalcium phosphate, calcium pyrophosphate, etc., in addition to the above-mentioned calcium phosphate compounds (β-type tricalcium phosphate, dicalcium phosphate and tetracalcium phosphate). Among them, amorphous hydroxyapatite may be contained.

Amorphous hydroxyapatite ( _Ca10 ( _PO4 ) ₆ (OH) ₂ ; sometimes abbreviated as amorphous HAP) serves as a scaffold for the formation of amorphous hydroxyapatite from calcium phosphate dibasic and calcium tetrabasic according to formula (I) above, and functions to promote the reaction by which amorphous hydroxyapatite is formed according to formula (I) above.

The content of amorphous hydroxyapatite is preferably 1 to 45% by mass, and more preferably 5 to 25% by mass, relative to 100% by mass of the total of β-type tricalcium phosphate, dicalcium phosphate, and tetracalcium phosphate in the calcium phosphate hardening composition. By setting the content of amorphous hydroxyapatite within the range of 1 to 45% by mass, amorphous hydroxyapatite can be produced more efficiently by the above formula (I).

The average particle size of the amorphous hydroxyapatite is preferably 0.01 to 50 μm, and more preferably 0.03 to 20 μm. By setting the average particle size of the amorphous hydroxyapatite within the range of 0.01 to 50 μm, the powder composed of amorphous hydroxyapatite can more reliably function as a scaffold.

The method for producing amorphous hydroxyapatite is not particularly limited, but examples include methods for obtaining amorphous hydroxyapatite using any of the known wet synthesis methods, dry synthesis methods, hydrothermal synthesis methods, etc.

(6) Other Additives The calcium phosphate composition according to the first embodiment (first paste and second paste) and the calcium phosphate composition according to the second embodiment (first paste, second paste, and third paste) may contain a hardening accelerator for promoting the reaction of the formula (I), a thickener for adjusting the viscosity of each paste and the calcium phosphate hardening composition obtained by mixing them, a stabilizer for stabilizing the thickener, etc. These additives may be contained in all of the pastes or only in any of the pastes, and are not particularly limited. The hardening accelerator, thickener, and stabilizer will be described in detail below.

(a) Curing Accelerator Examples of the curing accelerator include organic acids and their salts. The organic acid is not particularly limited, but examples thereof include monocarboxylic acids such as formic acid, acetic acid, and propionic acid, dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, and phthalic acid, oxymonocarboxylic acids such as hydroxybutyric acid, lactic acid, and salicylic acid, oxydicarboxylic acids such as malic acid and tartaric acid, and oxytricarboxylic acids such as citric acid. These can be used alone or in combination of two or more. Among these, dicarboxylic acids are preferred, and succinic acid is more preferred.

Dicarboxylic acids have two carboxyl groups in the molecule, so they have a high ability to capture dicalcium phosphate and tetracalcium phosphate, allowing dicalcium phosphate and tetracalcium phosphate to be uniformly dispersed in the calcium phosphate hardening composition.

Since succinic acid is stable and non-toxic, hardened calcium phosphate can be safely used as bone cement.

Examples of salts of organic acids include sodium acetate, sodium oxalate, disodium succinate, sodium lactate, sodium tartrate, sodium citrate, calcium propionate, calcium malonate, calcium malate, and potassium aspartate. These can be used alone or in combination of two or more.

Of these organic acid salts, sodium succinate is more preferable. Sodium succinate is highly soluble in water, so each paste can be easily prepared. In addition, sodium succinate is stable and non-toxic, so the hardened calcium phosphate material can be safely used as bone cement.

The hardening accelerator is preferably dissolved in the water contained in each paste before use. The hardening accelerator content is preferably 5 to 50% by mass, and more preferably 10 to 20% by mass or less, relative to the water. By setting the hardening accelerator content within the range of 5 to 50% by mass, the reaction of formula (I) can be more reliably promoted.

(b) Thickeners Examples of thickeners include sodium chondroitin sulfate, curdlan, guar gum, xanthan gum, glucomannan, carrageenan, gum arabic, and gum tragacanth, and one or more of these may be used in combination. Among these, sodium chondroitin sulfate is preferred. Since sodium chondroitin sulfate has particularly excellent water retention, it can more reliably promote the reaction of formula (I) in the calcium phosphate hardening composition.

The thickener is preferably dissolved in the water contained in each paste before use. The content of the thickener is preferably 1 to 10% by mass, more preferably 4 to 7% by mass, relative to the water. By setting the content of the thickener within the range of 1 to 10% by mass, the consistency of the prepared calcium phosphate hardenable composition can be more reliably set within the range described below.

(c) Stabilizers Examples of stabilizers include sodium hydrogen sulfite, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), hydroquinone, and propyl gallate, and one or more of these may be used in combination. Among these, sodium hydrogen sulfite is preferred. By using these stabilizers, the calcium phosphate hardening composition can be stored at room temperature when sodium chondroitin sulfate is used as a thickener.

The stabilizer is preferably dissolved in the water contained in each paste before use. The stabilizer content is preferably 0.1 to 2% by mass, and more preferably 0.2 to 1% by mass, relative to the water. By setting the stabilizer content within the range of 0.1 to 2% by mass, it is possible to accurately suppress or prevent alteration and deterioration of the thickener.

The time and temperature for mixing each paste are not particularly limited as long as the calcium phosphate hardening composition obtained by mixing becomes a paste, but are set, for example, to about 0.5 to 5 minutes and about 20 to 40°C.

(7) Consistency of calcium phosphate hardening composition The consistency of the calcium phosphate hardening composition obtained by mixing the first paste and the second paste of the calcium phosphate composition according to the first embodiment, and the first paste, the second paste and the third paste of the calcium phosphate composition according to the second embodiment is preferably 10 to 30 mm, more preferably 20 to 28 mm. When the consistency of the calcium phosphate hardening composition is in the range of 10 to 30 mm, the calcium phosphate hardening composition has a suitable consistency for use as a bone cement, so that the calcium phosphate hardening composition can be easily injected (embedded) into a bone defect or an implantation site (affected site) such as in a bone, and can be hardened quickly after injection. In addition, when the consistency of the calcium phosphate hardening composition is less than 10 mm, the calcium phosphate hardening composition has a high viscosity, so that it may not be efficiently injected into an implantation site (in a bone). If the consistency of the calcium phosphate hardening composition is greater than 30 mm, the viscosity of the bone calcium phosphate hardening composition is low, and therefore, when injected into the implantation site (intrabone), it may take a long time for the calcium phosphate hardening composition to harden.

The reproducibility of the consistency of the calcium phosphate hardening composition is preferably such that the coefficient of variation (Cv value) is 0.1 to 5%, more preferably 0.1 to 3%. When the coefficient of variation of the consistency is in the range of 0.1 to 5%, the consistency variation is small, so that even if the calcium phosphate hardening composition is prepared at different times and places, a calcium phosphate hardening composition of a constant consistency can be obtained with good reproducibility. If the coefficient of variation of the consistency is greater than 5%, the consistency variation becomes large, so that the consistency differs each time the calcium phosphate hardening composition is prepared, and there is a risk that a calcium phosphate hardening composition of a constant consistency cannot be obtained.

The hardening time of the calcium phosphate hardening composition is preferably 5 to 15 minutes, and more preferably 5 to 13 minutes. By setting the hardening time within this range, the length of time required for the surgeon to prepare the calcium phosphate hardening composition by mixing the first paste and the second paste in the operating room and then embed the calcium phosphate hardening composition in the implantation site (defect site) of the bone. Therefore, the procedure of embedding the calcium phosphate hardening composition can be performed more efficiently.

The setting time can be adjusted by appropriately setting the content and average particle size of each of the β-type tricalcium phosphate, dicalcium phosphate, and tetracalcium phosphate within the ranges described above, and by appropriately setting the type and content of the setting accelerator described above.

Such hardening calcium phosphate compositions can be used as medical materials for implantation in the body, such as bone cement for teeth and bones.

Although the calcium phosphate composition according to the first embodiment and the calcium phosphate composition according to the second embodiment have been described above, the present invention is not limited thereto.

For example, in the first paste, the second paste, and the third paste, each of the constituent materials contained therein, except for the essential materials β-type tricalcium phosphate, dicalcium phosphate, and tetracalcium phosphate, can be replaced with any other material that can exhibit a similar function, or any other constituent material can be added.

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1
<2. Paste-based calcium phosphate composition>
(1) Preparation of calcium phosphate compound
(a) Preparation of β-type tricalcium phosphate β-type tricalcium phosphate was synthesized by wet synthesis in which phosphoric acid was dropped into a calcium hydroxide suspension. The synthesized β-type tricalcium phosphate was heated to 1050°C over 8 hours, maintained at 1050°C (calcination temperature) for 4 hours, and returned to room temperature over 8 hours. The tricalcium phosphate was calcined by this heating, and a powder of β-type tricalcium phosphate was obtained. The composition of the obtained powder was analyzed by XRD (RINT-UltimaIII, Rigaku), and the mass ratio (α/β) of α-type tricalcium phosphate contained as an impurity in β-type tricalcium phosphate was 0.0158.

(b) Dicalcium phosphate Dicalcium phosphate ("calcium hydrogen phosphate dihydrate" manufactured by Junsei Chemical Co., Ltd.) was prepared as the dicalcium phosphate. This dicalcium phosphate was treated in an automatic mortar to obtain a powder of dicalcium phosphate.

To measure the particle size, a portion of the obtained powder was suspended in water and dispersed with ultrasonic waves, and the particle size of the powder present in the suspension was measured. The average particle size in the suspension was 25.17 μm. Note that this suspension was used only to measure the particle size, and the paste described below was prepared using dicalcium phosphate powder.

(c) Preparation of quaternary calcium phosphate
66.66 mol of calcium hydroxide was suspended in 6 L of water, and an aqueous solution of phosphoric acid, prepared by diluting 33.68 mol of phosphoric acid with water, was slowly added dropwise to the suspension while stirring. After the addition was completed, the mixture was left at room temperature (25°C) for one day, and then dried at 110°C for 24 hours using a dryer. The dried product was then pre-sintered at 900°C for two hours, and the pre-sintered body obtained was uniformly pulverized and further sintered at 1400°C for four hours. The sintered product obtained was pulverized to obtain a powder of tetracalcium phosphate.

To measure the particle size, a portion of the resulting quaternary calcium phosphate powder was suspended in water, and the resulting suspension was dispersed using ultrasonic waves. The average particle size in the suspension was 51.66 μm. Note that this suspension was used only to measure the particle size, and the paste described below was prepared using quaternary calcium phosphate powder.

(2) Preparation of an aqueous additive solution An aqueous additive solution was prepared by adding disodium succinate hexahydrate, sodium chondroitin sulfate, and sodium hydrogen sulfite to an appropriate amount of water while stirring, so that the concentrations of disodium succinate anhydrous were 12.972 g/mL, sodium chondroitin sulfate were 5.405 g/mL, and sodium hydrogen sulfite were 0.3 g/mL.

(3) Preparation of two-paste calcium phosphate compositions
(a) First paste Commercially available magnesium phosphate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) and dibasic calcium phosphate (manufactured by Junsei Chemical Co., Ltd.) treated in an automatic mortar were mixed in a ratio of 0.029:0.971 (mass ratio) and kneaded for 30 minutes in a kneading machine. This kneaded powder was mixed with the β-type tribasic calcium phosphate prepared in (1) above and the additive aqueous solution prepared in (2) above in a ratio of 0.898:0.062:0.325 (mass ratio) to obtain a first paste.

(b) Second paste The tetracalcium phosphate prepared in (1) above and the additive aqueous solution prepared in (2) above were mixed in a ratio (mass ratio) of 0.24:0.075 to obtain a second paste.

(4) Evaluation of calcium phosphate hardening composition At room temperature (24±1°C), 1.285 g of the first paste and 0.315 g of the second paste were mixed for 1 minute to prepare a calcium phosphate hardening composition. This calcium phosphate hardening composition hardened quickly. The same operation was repeated three times, and the average hardening time was 21 minutes (±1.5 minutes), confirming that the composition hardened well.

Example 2
<3. Paste-based calcium phosphate composition>
(a) First paste Commercially available magnesium phosphate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) and dibasic calcium phosphate (manufactured by Junsei Chemical Co., Ltd.) treated in an automatic mortar in the same manner as in Example 1 were mixed in a ratio (mass ratio) of 0.029:0.971, and kneaded for 30 minutes in a kneading machine. This kneaded powder was mixed with an aqueous additive solution prepared in the same manner as in Example 1 in a ratio (mass ratio) of 0.062:0.021 to obtain a first paste.

(b) Second paste Tetracalcium phosphate prepared in the same manner as in Example 1 and an aqueous additive solution prepared in the same manner as in Example 1 were mixed in a ratio (mass ratio) of 0.240:0.075 to obtain a second paste.

(c) Third paste: A β-type tricalcium phosphate prepared in the same manner as in Example 1 and an additive aqueous solution prepared in the same manner as in Example 1 were mixed in a ratio (mass ratio) of 0.898:0.304 to obtain a third paste.

The first paste to the third paste were mixed to prepare a calcium phosphate hardening composition under the same conditions and composition ratio as in Example 1. The obtained calcium phosphate hardening composition was hardenable in the same manner as the calcium phosphate hardening composition obtained in Example 1, and it was found that it can be used as the calcium phosphate composition of the present invention.

Example 3
<2. Paste-based calcium phosphate composition>
(a) First paste Commercially available magnesium phosphate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) and dibasic calcium phosphate (manufactured by Junsei Chemical Co., Ltd.) treated in an automatic mortar in the same manner as in Example 1 were mixed in a ratio (mass ratio) of 0.029:0.971, and kneaded for 30 minutes in a kneading machine. This kneaded powder was mixed with β-type tribasic calcium phosphate prepared in the same manner as in Example 1, and an aqueous additive solution prepared in the same manner as in Example 1 in a ratio (mass ratio) of 0.062:0.380:0.200 to obtain a first paste.

(b) Second paste Tetracalcium phosphate prepared in the same manner as in Example 1, β-type tricalcium phosphate prepared in the same manner as in Example 1, and an aqueous additive solution prepared in the same manner as in Example 1 were mixed in a ratio (mass ratio) of 0.240:0.518:0.200 to obtain a second paste.

A calcium phosphate hardening composition was prepared by mixing the first paste and the second paste prepared in Example 3 under the same conditions and composition ratio as in Example 1. The obtained calcium phosphate hardening composition was able to harden in the same manner as the calcium phosphate hardening composition obtained in Example 1.

The second paste prepared in Example 3 was good immediately after preparation, but its viscosity increased over time, and after 7 days it hardened, becoming less than optimal for mixing. XRD analysis (RINT-UltimaIII, Rigaku) of the paste after 7 days showed a slight change in composition.

Example 4
<2. Paste-based calcium phosphate composition>
β-type tricalcium phosphate synthesized in the same manner as in Example 1 was heated to 1100°C over 8 hours, maintained at 1100°C (firing temperature) over 4 hours, and returned to room temperature over 8 hours to obtain a powder of β-type tricalcium phosphate. When the composition of the obtained powder was analyzed by XRD, the mass ratio (α/β) of α-type tricalcium phosphate contained as an impurity in β-type tricalcium phosphate was 0.0394. A first paste was prepared in the same manner as in Example 1, except that the powder of β-type tricalcium phosphate obtained in this manner was used, and a hardening calcium phosphate composition was prepared in the same manner as in Example 1.

The first paste prepared in Example 4 was able to harden, but was slightly harder than that of Example 1. Therefore, it was found that the first paste of Example 1 was more suitable than the first paste of Example 4 when the injection needle of the syringe was thin, etc.

Example 5
<2. Paste-based calcium phosphate composition>
β-type tricalcium phosphate synthesized in the same manner as in Example 1 was heated to 1100°C over 4 hours, maintained at 1100°C (firing temperature) for 4 hours, and returned to room temperature over 4 hours to obtain a powder of β-type tricalcium phosphate. When the composition of the obtained powder was analyzed by XRD, the mass ratio (α/β) of α-type tricalcium phosphate contained as an impurity in β-type tricalcium phosphate was 0.0541. A first paste was prepared in the same manner as in Example 1, except that the powder of β-type tricalcium phosphate obtained in this manner was used, and a hardening calcium phosphate composition was prepared in the same manner as in Example 1.

The first paste prepared in Example 5 was hardenable, but was slightly harder than the first pastes of Examples 1 and 4. Therefore, the first pastes of Examples 1 and 4 are considered to be more preferable than the first paste of Example 5.

Example 6
<2. Paste-based calcium phosphate composition>
A first paste was prepared in the same manner as in Example 1, except that the dicalcium phosphate was not treated in an automatic mortar, but was mixed with a powder of β-type tricalcium phosphate, and the mixed powder was treated in an automatic mortar. A hardening calcium phosphate composition was prepared in the same manner as in Example 1. It was found that the first paste obtained in Example 6 was slightly harder than that obtained in Example 1. It was also found that the hardening calcium phosphate composition obtained in Example 6 had a shorter hardening time than the hardening calcium phosphate composition of Example 1. Therefore, it is considered that the calcium phosphate composition of Example 1 may be more suitable in terms of handling properties such as ease of injection into a small space, but when it is desired to shorten the hardening time, it is considered that the calcium phosphate composition of Example 6 may be more suitable.

Comparative Example 1
Instead of preparing the first and second pastes separately, the dicalcium phosphate, β-type tricalcium phosphate, tetracalcium phosphate, and additive aqueous solution prepared and adjusted in Example 1 were mixed to have the same composition as the calcium phosphate hardening composition prepared in Example 1 to prepare one paste containing them. This paste hardened and could not be injected from a syringe.

The calcium phosphate compound composition of the calcium phosphate compositions prepared in each Example is shown in Table 1-1 below, and the firing conditions and mass ratio α/β (mass ratio of α-type tricalcium phosphate contained in β-type tricalcium phosphate) of the β-type tricalcium phosphate used in each Example are shown in Table 1-2 below.

注(1)：乳鉢処理を行った第二リン酸カルシウムを使用した。
(2)：第二リン酸カルシウムとβ型第三リン酸カルシウムとを混合後、乳鉢処理して使用した。
(3)：乳鉢処理を行わない第二リン酸カルシウムを使用した。

Note (1): Mortar-treated dibasic calcium phosphate was used.
(2) Dicalcium phosphate and β-type tricalcium phosphate were mixed and then mortared before use.
(3) Dicalcium phosphate was used without mortar treatment.

注(1)：β型第三リン酸カルシウムに含まれるα型第三リン酸カルシウムの質量比

Note (1): Mass ratio of α-type tricalcium phosphate contained in β-type tricalcium phosphate

Claims (8)

A first paste and a second paste that can be hardened by mixing with the first paste,
the first paste containing dicalcium phosphate and the second paste containing tetracalcium phosphate;
A calcium phosphate composition, characterized in that only the first paste further contains β-type tricalcium phosphate. The calcium phosphate composition according to claim 1,
A calcium phosphate composition, characterized in that the average particle size of the dicalcium phosphate in the first paste is 1 to 50 μm. The calcium phosphate composition according to claim 1 or 2 ,
A calcium phosphate composition, characterized in that the first paste contains 4 to 10 parts by mass of dicalcium phosphate and 25 to 45 parts by mass of water relative to 100 parts by mass of β-type tricalcium phosphate. The calcium phosphate composition according to claim 3 ,
A calcium phosphate composition, characterized in that the second paste contains 20 to 40 parts by mass of water per 100 parts by mass of tetracalcium phosphate. The calcium phosphate composition according to any one of claims 1 to 4 ,
A calcium phosphate composition, characterized in that the contents of β-type tricalcium phosphate, dicalcium phosphate and tetracalcium phosphate in the mixture of the first paste and the second paste are 50 to 90 mass%, 2 to 10 mass% and 5 to 30 mass%, respectively, relative to 100 mass% in total of β-type tricalcium phosphate, dicalcium phosphate and tetracalcium phosphate. The calcium phosphate composition according to any one of claims 1 to 5 ,
A calcium phosphate composition, characterized in that the amount of α-type tricalcium phosphate contained in the mixture of the first paste and the second paste is 5% by mass or less of the amount of β-type tricalcium phosphate. A paste material used as a first paste for the calcium phosphate composition according to any one of claims 1 to 6 , comprising:
A paste material comprising 100 parts by mass of β-type tricalcium phosphate, 4 to 10 parts by mass of dicalcium phosphate, and 25 to 45 parts by mass of water. A paste material used as a second paste of the calcium phosphate composition according to any one of claims 1 to 6 , comprising:
A paste material comprising 100 parts by mass of tetracalcium phosphate and 20 to 40 parts by mass of water.